When CNS lesions develop, neuronal degeneration occurs locally but in regions that are remote, yet functionally connected, to the primary lesion site. This process, known as "remote damage," significantly affects long-term outcomes in many CNS pathologies, such as stroke, multiple sclerosis, and traumatic brain and spinal cord injuries. Remote damage can last several days or months after the primary lesion, providing a window during which therapeutic approaches can be implemented to effect neuroprotection. The recognition of the importance of remote damage in determining disease outcomes has prompted considerable interest in examining remote damage-associated mechanisms, most of which is derived from the potential of this research to develop innovative pharmacological approaches for preserving neurons and improving functional outcomes. To this end, the hemicerebellectomy (HCb) experimental paradigm has been instrumental in highlighting the complexity and variety of the systems that are involved, identifying mechanisms of life/death decisions, and providing a testing ground for novel neuroprotective approaches. Inflammation, oxidative stress, apoptosis, autophagy, and neuronal changes in receptor mosaics are several remote damage mechanisms that have been identified and examined using the HCb model. In this review, we discuss our current understanding of remote degeneration mechanisms and their potential for exploitation with regard to neuroprotective approaches, focusing on HCb studies.